The Center has focused on glutamatergic mechanisms, especially in the hippocampus, in experimental models to explore testable hypotheses about their involvement in the cognitive manifestations of schizophrenia. The over-arching hypothesis of the Center has been that hypofunction of a subpopulation of brain NMDA receptors contributes to the clinical features of schizophrenia. During the last 5 years, significant advances have been made that lend support to our hypotheses, including the development of animal models that more faithfully recreate the synaptic pathology of the disorder, the characterization of hippocampal memory processes in rodents, such as transitive inference, that are relevant to schizophrenia, and the identification of risk genes by others that affect glutamatergic neurotransmission. The Center consists of seven Projects and 3 Cores. Project 1: Benes has shown that amygdalar picrotoxin injection recreates in hippocampal CA2/3 neuropathologic changes similar to those in schizophrenia and will define the molecular and electrophysiologic consequences of this lesion. Project 2: Lisman will examine the interaction between dopamine and NMDA receptors in the hippocampus and their role in novelty detection, which is impaired in schizophrenia. Project 3: Eichenbaum will characterize the NMDA receptor's role in components of pragmatic memory known to be affected in schizophrenia. Project 4: Coyle has created mice with conditional knockouts of seririe racemase and glutamate carboxypeptidase II to determine the electrophysiologic and behavioral consequences of suppressing their expression jn young adulthood. Furthermore, they will examine the mechanisms of action of the protein encoded by G72, a risk gene in schizophrenia that reputedly enhances D-serine catabolism. Project 5: Yurgelun-Todd will use MRS to measure NAA and NAAG levels in the brains of schizophrenic subjects and animal models, and on BOLD signal changes in fMRI. Project 6: Goff will determine the efficacy of D-serine in schizophrenic patients receiving concurrent antipsychotics and will correlate treatment responses to relevant genotypes such as GCPII, G72 and GRM3. Project 7: Javitt will evaluate the effects of D-serine treatment on sensory processing measures and higher neurocognitive disturbances in prodromal and established schizophrenics. Computational Core: Hasselmo will develop computational models based on the findings of the Center. Biostatistical Core: Lange will provide statistical support for Center investigators. Administrative Core: Coyle will provide scientific oversight and budgetary administration to insure that the goals are achieved.